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44


Relapsing White Matter Disease and Subclinical Optic Neuropathy: From the National Multiple Sclerosis Society Case Conference Proceedings

O'Neill, Kimberly A; Dugue, Andrew; Abreu, Nicolas J; Balcer, Laura J; Branche, Marc; Galetta, Steven; Graves, Jennifer; Kister, Ilya; Magro, Cynthia; Miller, Claire; Newsome, Scott D; Pappas, John; Rucker, Janet; Steigerwald, Connolly; William, Christopher M; Zamvil, Scott S; Grossman, Scott N; Krupp, Lauren B
A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.
PMID: 38181317
ISSN: 2332-7812
CID: 5628442

CLN2 disease resulting from a novel homozygous deep intronic splice variant in TPP1 discovered using long-read sequencing

Steigerwald, Connolly; Borsuk, Jill; Pappas, John; Galey, Miranda; Scott, Anna; Devaney, Joseph M; Miller, Danny E; Abreu, Nicolas J
Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive neurodegenerative disorder with enzyme replacement therapy available. We present two siblings with a clinical diagnosis of CLN2 disease, but no identifiable TPP1 variants after standard clinical testing. Long-read sequencing identified a homozygous deep intronic variant predicted to affect splicing, confirmed by clinical DNA and RNA sequencing. This case demonstrates how traditional laboratory assays can complement emerging molecular technologies to provide a precise molecular diagnosis.
PMID: 37922835
ISSN: 1096-7206
CID: 5612782

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature

Parra, Alejandro; Rabin, Rachel; Pappas, John; Pascual, Patricia; Cazalla, Mario; Arias, Pedro; Gallego-Zazo, Natalia; Santana, Alfredo; Arroyo, Ignacio; Artigas, Mercè; Pachajoa, Harry; Alanay, Yasemin; Akgun-Dogan, Ozlem; Ruaud, Lyse; Couque, Nathalie; Levy, Jonathan; Porras-Hurtado, Gloria Liliana; Santos-Simarro, Fernando; Ballesta-Martinez, Maria Juliana; Guillén-Navarro, Encarna; Muñoz-Hernández, Hugo; Nevado, Julián; Tenorio-Castano, Jair; Lapunzina, Pablo
SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.
PMCID:10297832
PMID: 37372360
ISSN: 2073-4425
CID: 5538592

Biochemical characterization of two novel mutations in the human high-affinity choline transporter 1 identified in a patient with congenital myasthenic syndrome

Rizvi, Midhat; Truong, Tina K; Zhou, Janet; Batta, Manav; Moran, Ellen S; Pappas, John; Chu, Mary Lynn; Caluseriu, Oana; Evrony, Gilad D; Leslie, Elaine M; Cordat, Emmanuelle
Congenital myasthenic syndrome (CMS) is a heterogeneous condition associated with 34 different genes, including SLC5A7, which encodes the high affinity choline transporter 1 (CHT1). CHT1 is expressed in presynaptic neurons of the neuromuscular junction where it uses the inward sodium gradient to re-uptake choline. Bi-allelic CHT1 mutations often lead to neonatal lethality, and less commonly to non-lethal motor weakness and developmental delays. Here, we report detailed biochemical characterization of two novel mutations in CHT1, p.I294T and p.D349N, that we identified in an 11 year-old patient with a history of neonatal respiratory distress, and subsequent hypotonia and global developmental delay. Heterologous expression of each CHT1 mutant in human embryonic kidney cells showed two different mechanisms of reduced protein function. The p.I294T CHT1 mutant transporter function was detectable, but its abundance and half-life were significantly reduced. In contrast, the p.D349N CHT1 mutant was abundantly expressed at the cell membrane, but transporter function was absent. The residual function of the p.I294T CHT1 mutant may explain the non-lethal form of CMS in this patient, and the divergent mechanisms of reduced CHT1 function that we identified may guide future functional studies of the CHT1 myasthenic syndrome. Based on these in vitro studies that provided a diagnosis, treatment with cholinesterase inhibitor together with physical and occupational therapy significantly improved the patient's strength and quality of life.
PMID: 36611016
ISSN: 1460-2083
CID: 5433572

Impaired protein hydroxylase activity causes replication stress and developmental abnormalities in humans

Fletcher, Sally C; Hall, Charlotte L; Kennedy, Tristan J; Pajusalu, Sander; Wojcik, Monica H; Boora, Uncaar; Li, Chan; Oja, Kaisa Teele; Hendrix, Eline; Westrip, Christian Ae; Andrijes, Regina; Piasecka, Sonia K; Singh, Mansi; El-Asrag, Mohammed E; Ptasinska, Anetta; Tillmann, Vallo; Higgs, Martin R; Carere, Deanna Alexis; Beggs, Andrew D; Pappas, John; Rabin, Rachel; Smerdon, Stephen J; Stewart, Grant S; Õunap, Katrin; Coleman, Mathew L
Although protein hydroxylation is a relatively poorly characterized post-translational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a 'JmjC-only' protein hydroxylase that is essential for murine embryonic development and viability. However, no germline variants in JmjC-only hydroxylases, including JMJD5, have yet been described that are associated with any human pathology. Here we demonstrate that biallelic germline JMJD5 pathogenic variants are deleterious to JMJD5 mRNA splicing, protein stability, and hydroxylase activity, resulting in a human developmental disorder characterised by severe failure to thrive, intellectual disability, and facial dysmorphism. We show that the underlying cellular phenotype is associated with increased DNA replication stress and that this is critically dependent on the protein hydroxylase activity of JMJD5. This work contributes to our growing understanding of the role and importance of protein hydroxylases in human development and disease.
PMID: 36795492
ISSN: 1558-8238
CID: 5432172

Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration

Muffels, Irena J J; Schene, Imre F; Rehmann, Holger; Massink, Maarten P G; van der Wal, Maria M; Bauder, Corinna; Labeur, Martha; Armando, Natalia G; Lequin, Maarten H; Houben, Michiel L; Giltay, Jaques C; Haitjema, Saskia; Huisman, Albert; Vansenne, Fleur; Bluvstein, Judith; Pappas, John; Shailee, Lala V; Zarate, Yuri A; Mokry, Michal; van Haaften, Gijs W; Nieuwenhuis, Edward E S; Refojo, Damian; van Wijk, Femke; Fuchs, Sabine A; van Hasselt, Peter M
Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132-requiring upregulation of neddylation to restore proteasomal function and proteasomal stress-led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature-delayed closure of the ischiopubic rami-correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.
PMID: 36608681
ISSN: 1537-6605
CID: 5400362

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Dias, Kerith-Rae; Carlston, Colleen M; Blok, Laura E R; De Hayr, Lachlan; Nawaz, Urwah; Evans, Carey-Anne; Bayrak-Toydemir, Pinar; Htun, Stephanie; Zhu, Ying; Ma, Alan; Lynch, Sally Ann; Moorwood, Catherine; Stals, Karen; Ellard, Sian; Bainbridge, Matthew N; Friedman, Jennifer; Pappas, John G; Rabin, Rachel; Nowak, Catherine B; Douglas, Jessica; Wilson, Theodore E; Guillen Sacoto, Maria J; Mullegama, Sureni V; Palculict, Timothy Blake; Kirk, Edwin P; Pinner, Jason R; Edwards, Matthew; Montanari, Francesca; Graziano, Claudio; Pippucci, Tommaso; Dingmann, Bri; Glass, Ian; Mefford, Heather C; Shimoji, Takeyoshi; Suzuki, Toshimitsu; Yamakawa, Kazuhiro; Streff, Haley; Schaaf, Christian P; Slavotinek, Anne M; Voineagu, Irina; Carey, John C; Buckley, Michael F; Schenck, Annette; Harvey, Robert J; Roscioli, Tony
PURPOSE/OBJECTIVE:ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS:An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS:ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION/CONCLUSIONS:We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.
PMID: 35916866
ISSN: 1530-0366
CID: 5287932

Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder

Meuwissen, Marije; Verstraeten, Aline; Ranza, Emmanuelle; Iwaszkiewicz, Justyna; Bastiaansen, Maaike; Mateiu, Ligia; Nemegeer, Merlijn; Meester, Josephina A N; Afenjar, Alexandra; Amaral, Michelle; Ballhausen, Diana; Barnett, Sarah; Barth, Magalie; Asselbergh, Bob; Spaas, Katrien; Heeman, Bavo; Bassetti, Jennifer; Blackburn, Patrick; Schaer, Marie; Blanc, Xavier; Zoete, Vincent; Casas, Kari; Courtin, Thomas; Doummar, Diane; Guerry, Frédéric; Keren, Boris; Pappas, John; Rabin, Rachel; Begtrup, Amber; Shinawi, Marwan; Vulto-van Silfhout, Anneke T; Kleefstra, Tjitske; Wagner, Matias; Ziegler, Alban; Schaefer, Elise; Gerard, Benedicte; De Bie, Charlotte I; Holwerda, Sjoerd J B; Abbot, Mary Alice; Antonarakis, Stylianos E; Loeys, Bart
PURPOSE/OBJECTIVE:CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. METHODS:Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. RESULTS:Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. CONCLUSION/CONCLUSIONS:We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function.
PMID: 35499524
ISSN: 1530-0366
CID: 5215882

De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+ regulation

Halvorsen, Matthew; Gould, Laura; Wang, Xiaohan; Grant, Gariel; Moya, Raquel; Rabin, Rachel; Ackerman, Michael J; Tester, David J; Lin, Peter T; Pappas, John G; Maurano, Matthew T; Goldstein, David B; Tsien, Richard W; Devinsky, Orrin
Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.
PMID: 34930847
ISSN: 1091-6490
CID: 5108732

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Schirwani, Schaida; Albaba, Shadi; Carere, Deanna Alexis; Guillen Sacoto, Maria J; Milan Zamora, Francisca; Si, Yue; Rabin, Rachel; Pappas, John; Renaud, Deborah L; Hauser, Natalie; Reid, Evan; Blanchet, Patricia; Foulds, Nichola; Dixit, Abhijit; Fisher, Richard; Armstrong, Ruth; Isidor, Bertrand; Cogne, Benjamin; Schrier Vergano, Samantha; Demirdas, Serwet; Dykzeul, Natalie; Cohen, Julie S; Grand, Katheryn; Morel, Dayna; Slavotinek, Anne; Albassam, Hessa F; Naik, Swati; Dean, John; Ragge, Nicola; Cinzia, Costa; Tedesco, Maria Giovanna; Harrison, Rachel E; Bouman, Arjan; Palen, Emily; Challman, Thomas D; Willemsen, Marjolein H; Vogt, Julie; Cunniff, Christopher; Bergstrom, Katherine; Walia, Jagdeep S; Bruel, Ange-Line; Kini, Usha; Alkuraya, Fowzan S; Slegesky, Valerie; Meeks, Naomi; Girotto, Paula; Johnson, Diana; Newbury-Ecob, Ruth; Ockeloen, Charlotte W; Prontera, Paolo; Lynch, Sally Ann; Li, Dong; Graham, John M; Balasubramanian, Meena
The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
PMID: 34436830
ISSN: 1552-4833
CID: 5011592